VENETOCLAX

Details

Stereochemistry	ACHIRAL
Molecular Formula	C45H50ClN7O7S
Molecular Weight	868.439
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1(C)CCC(CN2CCN(CC2)C3=CC=C(C(=O)NS(=O)(=O)C4=CC=C(NCC5CCOCC5)C(=C4)[N+]([O-])=O)C(OC6=CN=C7NC=CC7=C6)=C3)=C(C1)C8=CC=C(Cl)C=C8

InChI

InChIKey=LQBVNQSMGBZMKD-UHFFFAOYSA-N

InChI=1S/C45H50ClN7O7S/c1-45(2)15-11-33(39(26-45)31-3-5-34(46)6-4-31)29-51-17-19-52(20-18-51)35-7-9-38(42(24-35)60-36-23-32-12-16-47-43(32)49-28-36)44(54)50-61(57,58)37-8-10-40(41(25-37)53(55)56)48-27-30-13-21-59-22-14-30/h3-10,12,16,23-25,28,30,48H,11,13-15,17-22,26-27,29H2,1-2H3,(H,47,49)(H,50,54)

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf | https://www.ncbi.nlm.nih.gov/pubmed/28057737 | https://www.ncbi.nlm.nih.gov/pubmed/27698099

Venetoclax (trade name Venclexta, also known as ABT-199) is a selective and orally bioavailable small-molecule inhibitor of BCL-2, an antiapoptotic protein. BCL-2 and its related proteins BCL-XL and MCL-1 bind to and sequester pro-apoptotic signals in the cell, causing a down-regulation of apoptosis. As an oncogene and an important regulator of apoptosis, BCL-2 overexpression therefore results in increased tumor cell survival and resistance to chemotherapy. FDA approved Venetoclax in April 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. Also this drug in phase 3 clinical trial in combination therapy for the treatment patients with refractory myeloma and Acute Myeloid Leukemia. Common side effects include neutropenia, nausea, anemia, diarrhea, upper respiratory tract infection. Major side effects include tumor lysis syndrome and severe neutropenia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Apoptosis regulator Bcl-2 19 Target ID: CHEMBL4860 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23291630	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Chronic lymphocytic leukemia 59 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	Primary	Approved 8429	VENCLEXTA Approved Use VENCLEXTA is a BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Launch Date 2016
Refractory myeloma 2 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28057737	Primary	Phase III 656	Unknown Approved Use Unknown
Acute myeloid leukemia 136 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27698099	Primary	Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
2.1 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	400 mg 1 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: LOW-FAT
1.43 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27558232	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

AUC

Value	Dose	Co-administered	Analyte	Population
32.8 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	400 mg 1 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: LOW-FAT
30.2 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27558232	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

T_1/2

Value	Dose	Co-administered	Analyte	Population
14.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27558232	400 mg 1 times / day multiple, oral dose: 400 mg route of administration: Oral experiment type: MULTIPLE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT

F_unbound

Value	Dose	Co-administered	Analyte	Population
1% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	400 mg 1 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		VENETOCLAX plasma	Homo sapiens population: UNKNOWN age: ADULT sex: UNKNOWN food status: LOW-FAT

Doses

Dose	Population	Adverse events
1200 mg 1 times / day steady, oral Highest studied dose Dose: 1200 mg, 1 times / day Route: oral Route: steady Dose: 1200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/28095146	unhealthy, 66 years (range: 25 - 86 years) n = 52 Health Status: unhealthy Condition: Relapsed or Refractory Non-Hodgkin Lymphoma Age Group: 66 years (range: 25 - 86 years) Sex: M+F Population Size: 52 Sources: https://pubmed.ncbi.nlm.nih.gov/28095146	Disc. AE: Nausea, Diarrhea... Other AEs: Nausea, Diarrhea... AEs leading to discontinuation/dose reduction: Nausea (5 patients) Diarrhea (4 patients) Other AEs: Nausea (grade 1-2, 53%) Diarrhea (grade 1-2, 53%) Diarrhea (grade 3-4, 2%) Fatigue (grade 1-2, 49%) Fatigue (grade 3-4, 6%) Decreased appetite (grade 1-2, 29%) Vomiting (grade 1-2, 24%) Constipation (grade 1-2, 18%) Headache (grade 1-2, 20%) Anemia (grade 1-2, 10%) Anemia (grade 3-4, 8%) Cough (grade 1-2, 10%) Neutropenia (grade 1-2, 12%) Neutropenia (grade 3-4, 8%) Back pain (grade 1-2, 16%) Back pain (grade 3-4, 2%) Upper respiratory tract infection (grade 1-2, 8%) Sources: https://pubmed.ncbi.nlm.nih.gov/28095146
400 mg 1 times / day steady, oral Recommended Dose: 400 mg, 1 times / day Route: oral Route: steady Dose: 400 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	unhealthy, 66 years (range: 29 - 85 years) n = 240 Health Status: unhealthy Condition: CLL Age Group: 66 years (range: 29 - 85 years) Sex: M+F Population Size: 240 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf	Disc. AE: Neutropenia, Thrombocytopenia... Other AEs: Neutropenia, Neutrophil count decreased... AEs leading to discontinuation/dose reduction: Neutropenia (grade 3-4, 41%) Thrombocytopenia (grade 3-4, 15%) Febrile neutropenia (serious, 2%) Anemia hemolytic autoimmune (serious, 2%) Other AEs: Neutropenia (all grades, > 20) Neutrophil count decreased (all grades, 45%) Neutrophil count decreased (grade 3-4, 41%) Diarrhea (all grades, > 20) Diarrhea (grade 3-4, <1%) Nausea (grade 3-4, <1%) Nausea (all grades, > 20) Anemia (all grades, > 20) Anemia (grade 3-4, 18%) Hemoglobin decreased (all grades, 29%) Hemoglobin decreased (grade 3-4, 18%) Upper respiratory tract infection (all grades, > 20) Thrombocytopenia (all grades, > 20) Platelet count decreased (all grades, 22%) Platelet count decreased (grade 3-4, 15%) Fatigue (all grades, > 20) Fatigue (grade 3-4, 2%) Pneumonia (serious, 2%) Pyrexia (serious, 2%) Anemia (serious, 2%) Tumor lysis syndrome (serious, 2%) Vomiting (all grades, 15%) Vomiting (grade 3-4, <1%) Constipation (all grades, 14%) Peripheral edema (all grades, 11%) Peripheral edema (grade 3-4, <1%) Upper respiratory tract infection (all grades, 22%) Upper respiratory tract infection (grade 3-4, 1%) Pneumonia (all grades, 8%) Pneumonia (grade 3-4, 5%) Hypokalemia (all grades, 12%) Hypokalemia (grade 3-4, 4%) Back pain (all grades, 10%) Back pain (grade 3-4, <1%) Headache (all grades, 15%) Headache (grade 3-4, <1%) Cough (all grades, 13%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf
600 mg 1 times / day steady, oral Dose: 600 mg, 1 times / day Route: oral Route: steady Dose: 600 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/29018077	unhealthy n = 9 Health Status: unhealthy Condition: relapsed/refractory MM Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/29018077	DLT: Nausea, Abdominal pain... Dose limiting toxicities: Nausea (grade 3, 1 patient) Abdominal pain (grade 2, 1 patient) Vomiting (grade 3, 1 patient) Epigastralgia (grade 3, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/29018077

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461 CYP2C8 911 CYP1A2 1524 CYP2B6 810 CYP2C19 1478 BCRP 699	CYP3A4/5 85 P-gp 1537 BCRP 561 OATP1B1 406 OATP1B3 350	CYP1A2 701 CYP2B6 547

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	no
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	no
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	no
BCRP 773	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes [IC50 0.13 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	yes [IC50 0.14 uM]
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes [IC50 0.79 uM]
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=36 Page: 36.0	yes [IC50 0.82 uM]

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4/5 85	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	major	yes (co-administration study) Comment: Co-administration of ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) increased venetoclax Cmax and AUCX by 2.3- and 6.4-fold, respectively. Co-administration of moderate CYP3A4/5 inhibitors showed a smaller effect on venetoclax exposrue (40 to 60% increase in Cmax and AUCo-24)- Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=6 Page: 6.0
OATP1B1 406	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=32 Page: 32.0	no
OATP1B3 350	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=40 Page: 40.0	no
BCRP 561	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=37 Page: 37.0	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=6 Page: 6.0	yes	yes (co-administration study) Comment: Venetoclax exposure also increased (Cmax t 106%, AUCX T 78%) after co-administration of single dose of rifampin, presumably due to the inhibition of P-gp by rifampin. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000ClinPharmR.pdf#page=6 Page: 6.0

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208573Orig1s000PharmR.pdf#page=43 Page: 43.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:133021	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:133021
ChemicalBook	CB62645962	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB62645962
MolPort	MolPort-028-720-431	https://www.molport.com/shop/molecule-link/MolPort-028-720-431
Selleck Chemicals	abt-199	http://www.selleckchem.com/products/abt-199.html
ZINC	ZINC000150338755	http://zinc15.docking.org/substances/ZINC000150338755

PubMed

Title	Date	PubMed
		252160763
Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.	1988 Sep 29	3262202
Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides.	2002 Nov	12445555
Novel therapies for chronic lymphocytic leukemia.	2004 Jun	15010151
An inhibitor of Bcl-2 family proteins induces regression of solid tumours.	2005 Jun 2	15902208
Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.	2008 Nov 13	18841882
The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib.	2010 Oct	20799354
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.	2013 Feb	23291630
Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.	2015 Sep	26214592

Patents

Sample Use Guides

In Vivo Use Guide

Initiate therapy with VENCLEXTA (venetoclax) at 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. VENCLEXTA tablets should be taken orally once daily with a meal and water.

Route of Administration: Oral

In Vitro Use Guide

ABT-199 (Venetoclax) shows less sensitivity to Bcl-xL, Mcl-1 and Bcl-w with Ki of 48 nM, > 444 nM and 245 nM, respectively. ABT-199 potently inhibits FL5.12-Bcl-2 cells, RS4;11 cells with EC50 of 4 nM and 8 nM, while shows low activity against FL5. ABT-199 also induces apoptosis in CLL with an average EC50 of 3.0 nM.

Name

Type

Language

VENETOCLAX

Official Name

English

RG7601

Code

English

ABT-199

Code

English

venetoclax [INN]

Common Name

English

VENCLEXTA

Brand Name

English

VENETOCLAX [ORANGE BOOK]

Common Name

English

Venetoclax [WHO-DD]

Common Name

English

VENETOCLAX [USAN]

Common Name

English

4-(4-((2-(4-CHLOROPHENYL)-4,4-DIMETHYLCYCLOHEX-1-EN-1-YL)METHYL)PIPERAZIN-1-YL)-N-((3-NITRO-4-((TETRAHYDRO-2HPYRAN-4-YLMETHYL) AMINO)PHENYL)SULFONYL)-2-(1H-PYRROLO(2,3-B)PYRIDIN-5-YLOXY)BENZAMIDE

Common Name

English

RG-7601

Code

English

VENETOCLAX [MI]

Common Name

English

BENZAMIDE, 4-(4-((2-(4-CHLOROPHENYL)-4,4-DIMETHYL-1-CYCLOHEXEN-1-YL)METHYL)-1-PIPERAZINYL)-N-((3-NITRO-4-(((TETRAHYDRO-2H-PYRAN-4-YL)METHYL)AMINO)PHENYL)SULFONYL)-2-(1H-PYRROLO(2,3-B)PYRIDIN-5-YLOXY)-

Common Name

English

VENETOCLAX [JAN]

Common Name

English

4-(4-((2-(4-CHLOROPHENYL)-4,4-DIMETHYLCYCLOHEX-1-EN-1-YL)METHYL)PIPERAZIN-1-YL)-N-((3-NITRO-4-((TETRAHYDRO-2H-PYRAN-4-YLMETHYL)AMINO)PHENYL)SULFONYL)-2-(1H-PYRROLO(2,3-B)PYRIDIN-5-YLOXY)BENZAMIDE

Systematic Name

English

GDC-0199

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

375612